Methamphetamine (METH) dependence has drastic consequences in terms of psychological and physical health, and places great economic and legal burdens on communities. METH abuse and dependence, long a serious problem in the West, is now spreading in near-epidemic proportions to the eastern United States and has experienced dramatic growth in South Carolina in the past five years. Cue-elicited drug craving is believed to be a critical component in drug seeking, and relapse in the natural environment. Investigators have suggested that a critical characteristic of addiction is increased cue saliency and enhanced cue-drug memory circuits which overwhelm inhibitory control normally exerted by the prefrontal cortex for natural cues and reinforcers. Medication development for METH treatment is progressing, but much remains to be learned about the fundamental neurobiology of METH addiction. Cue exposure coupled with functional neuroimaging techniques (PET, SPECT, fMRI) has been extremely useful in elucidating brain circuitry for nicotine, cocaine, and alcohol-dependent individuals. It has been suggested that identifying pharmacologic agents that alter human cue-induced craving and drug-seeking as measured with functional brain imaging could well be an effective screening tool for potential pharmacotherapeutic agents and a productive path for drug development. No circuitry map exists for METH cue activation in either preclinical models or human clinical imaging. Preclinical studies in rodents indicate that METH-treated animals may have impaired extinction learning. Our group has used the technique of fMRI to evaluate regional brain circuitry changes with alcohol and, more recently, cocaine cue stimulation. Working in close concert with Project #1, the primary aims of this proposal are to develop procedures to assess brain circuitry through fMRI under conditions of cue-generated craving and cue extinction in non-treatment-seeking METH-dependent subjects. Using BOLD fMRI, multiple fMRIs will be assessed over time to measure changes in circuit activation with exposure to METH cues and neutral cues. We propose to recruit 60 non-treatment-seeking METH-dependent males and females of all ethnic and racial groups between ages 18 and 50 to participate in this study. This study will consist of 3 phases: 1) outpatient screening;2) inpatient cue-exposure with repeated fMRIs overtime during METH and neutral cue exposure;and 3) Two weeks of outpatient follow-up. This project will work closely with Project #4 in the development of METH-specific environmental cues and with Project #1 in identifying specific circuits underlying METH cue-reactivity and extinction. The bidirectional exchange of information between human and animal studies in identifying the critical circuitry involved in these important functions will accelerate the pace of discovery.